The treatment of Gram-negative bacteria has intensified with many development programs during its golden era from the 1960s through to the 1980s. However, with the increasing Gram-positive bacteria infections, such as MRSA (Methicillin-resistant Staphylococcus aureus) in the 1990s, the Gram-negative researches were overshadowed. Since late 2000, due to the growing concern of the lack of multidrug-resistant Gram-negative bacteria treatment, the Gram-negative bacteria research re-gained its interest. According to the recent publication by the Infectious Diseases Society of America (IDSA), The European Centre for Disease Prevention and Control (ECDC), and the European Medicines Agency (EMEA), there are only 8 effective drugs against Gram-negative bacteria worldwide. Especially the multidrug-resistant Gram-negative bacteria new drug discovery is extremely scarce.
In particular, the recently discovered NDM-1 (New Delhi metalo-beta-lactamase) is rapidly spreading and became a threat to international community. The NDM-1 mainly appears in Gram-negative bacteria, and currently colistin and tigecycline are the only two effective drugs. However, these drugs are not readily used due to their toxicity and side effects. Thus urgent needs to replace these two drugs are in demand. The rapid spread of these pathogens is not just a burden on few affected countries but on every country where an international join effort is a must to control such spread.
Already in 2004, the Infectious Diseases Society of America (IDSA) had published a report called the “Bad Bugs, No Drugs.” A hit list was published in this report as the current global rate of resistance increases. The list is based on the morbidity, mortality with high pathogen, and absence of the effective drug therapy. Amongst the list, 3 of them are the Gram-negative bacteria: P. aeruginosa, A. baumannii, and K. pneumoniae isolates. They require government's support as they create serious disease outbreak problems. Currently, there are few classes of drug available against these bacteria, such as cephalosporins, carbapenems, aminoglycosides, and tigecyclines. However, there are no effective drugs available against the resistant stains, and especially against acinetobacter, tigecyclines is the only effective class of drug.
In 2006, the multidrug-resistant K. pneumoniae was reported in patients with XDR-KP only in the eastern part of the United States, but more recently, it spread throughout the rest of the country. In case of acinetobacter, the infection spread nationwide by the soldiers who were previously deployed to Middle Eastern countries. Carbapenems is mainly used as the leading treatment, but there is rapid increase in carbapenems resistant stains, thus it is left with any effective treatment.
As the demand increases for Gram-negative bacteria treatments, pharmaceutical companies are showing strong interest, but only few antibiotics are in development. Among them is β-lactam inhibitors, and some noteworthy compounds are CEF-104 and CAZ-104 from Novexel, CAX-201 from Cubist, and one compound from each of the following classes: Polymyxin, tetracycline and aminoglycoside. Among effective acinetobacters, there are PTK-0796, a tetracycline class, and CB-182,804, a polymyxin derivative. However, these two compounds are not widely used due to their toxicity issues in their safety profile.
Currently cephalosporin and carbapenem are the two most widely used Gram-negative antibiotics classes. Within carbapenem class, imipenem and meropenem are the market dominating compounds, but the predominant market leading compounds are the generic drugs. Ceftobiprole was the most promising candidate within the cephalosporin class, but unfortunately its development program was discontinued. Therefore, within the cephalosporin class, generic compounds and combi-therapy will be the main treatment options.
One of the reason why the multidrug-resistant Gram-negative bacteria causes serious problem is that most of the strains show resistance to antibiotics currently in use, leaving many strains untreatable. There are several reasons for the increase in resistant strains, but in case of P. aeruginosa, the mutations in outer membrane and porin channel are the main causes of the resistance. Due to these mutations, many β-lactam inhibitors are an not able to enter into Gram-negative bacteria. To overcome these resistances caused by the mutations in outer membrane and in porin channel, siderophore driven antibiotic was being heavily researched. Iron ions are essential ingredient for the growth of bacteria. These iron ions have high affinity to siderosphore, and bacteria produces siderophore to bind these iron ions and internalize them into their system. Bacteria have siderophore recognizing cell membrane receptors to bind and internalize iron ions. FIG. 1 represents bacteria's binding mechanism to siderophore and iron ions using its membrane receptors.
Therefore, siderophore-mimicking moiety can be attached to an antibiotic, and bacteria's siderophore receptor can bind to antibiotic. Bacteria will then internalize the antibiotic. This internalization is much easier then the typical porin channel mediated antibiotic internalization, and it is also immune to resistancy cause by the porin channel mutation. FIG. 2 represents the internalization of iron ions by biding of siderophore to bacteria's receptor.
Although there were many research efforts that went into overcoming resistancy problems by incorporating siderophore moiety, not many have succeeded this far. One of the reasons is that catechol is mainly used for siderophore moiety, but it is rapidly transformed by catechol O-methyl transferase (COMT) and can no longer be bind to siderophore receptor. Many catechol modifications have been made to overcome this issue, but they often resulted in low efficacy and, or high toxicity. There were also dramatic variations on the location of the siderophore moiety in antibiotic. Therefore, there are critical needs to develop more potent antimicrobial activity against Gram-negative bacteria drug than currently existing cephalosporins. Especially there are urgent needs to develop cephalosporins against P. aeruginosa and K. pneumonia resistant strains.